Preparation of saturated ketone morphinan compounds having low metal content

1. A process for preparing a compound having Formula (II), wherein the compound having Formula (II) is substantially metal-free:

the process comprising:

a) contacting a compound having Formula (I) with a transition metal catalyst to form a reaction product comprising the compound having Formula (II); and

b) contacting the reaction product of step (a) with a metal scavenger such that the metal scavenger binds the transition metal catalyst, thereby yielding the substantially metal-free compound having Formula (II), the compound of Formula (I) being:

wherein:

A is oxygen;

R 1 , R 2 , and R 3 are independently chosen from hydrogen, halogen, hydroxy, protected hydroxy, {—}SH, {—}SR 1611 , {—}OR 1611 , and {—}NR 1611 R 1612 , hydrocarbyl, and substituted hydrocarbyl;

R 5 , R 7 , R 8 , R 9 , R 10a , R 10b , R 14 , R 15a , R 15b , R 16a , R 16b , and R 17 are independently chosen from hydrogen, halogen, hydroxy, {—}SH, {—}SR 1611 , {—}OR 1611 , and {—}NR 1611 R 1612 , hydrocarbyl, and substituted hydrocarbyl; provided that any of R 10a and R 10b , R 15a and R 15b , and R 16a and R 16b may together form a moiety selected from the group consisting of {═}O, {═}S, and {═}NR 1613 ; and

R 1611 , R 1612 , an R 1613 are independently chosen from hydrocarbyl, and substituted hydrocarbyl.

2. The process of claim 1 , wherein R 1 , R 2 , R 5 , R 7 , R 8 , R 9 , R 10a , R 10b , R 15a , R 15b , R 16a , and R 16b are hydrogen; R 3 is chosen from hydroxy, protected hydroxy, alkyloxy, and acyloxy; R 14 is hydrogen or hydroxy; and R 17 is chosen from hydrogen, alkyl, cycloalkyl, cycloalkylmethyl, allyl, and aryl.

3. The process of claim 2 , wherein R 3 is hydroxy or methyoxy; R 14 is hydrogen; and R 17 is methyl.

4. The process of claim 1 , wherein the transition metal catalyst is chosen from a transition metal element, a transition metal salt, and a transition metal complex; and comprises a transition metal chosen from iridium, nickel, osmium, palladium, platinum, rhodium, and ruthenium.

5. The process of claim 4 , wherein the transition metal salt comprises an anion chosen from an acetate, an acetyacetonate, an alkoxide, a butyrate, a carbonyl, a dioxide, a halide, a hexonate, a hydride, a mesylate, an octanate, a nitrate, a nitrosyl halide, a nitrosyl nitrate, a sulfate, a sulfide, a sulfonate, a phosphate, a trifluoromethanesulfonate, a trimethylacetate, a tosylate, and combinations thereof.

6. The process of claim 4 , wherein the transition metal complex is chosen from a bis(allyl)-ruthenium complex selected from {Ru(η 3 :η 3 -C 10 H 16 )(μ-Cl)Cl} 2 , Ru(η 3 :η 2 :η 3 -C 12 H 18 )Cl 2 , and {Ru(η 3 :η 3 -C 12 H 20 )(μ-Cl)Cl} 2 ; and a phosphine complex selected form (phosphine) x PdCl 2 , (PPh 3 ) 4 Pd, RuCl 2 (PPh 3 ) 3 , RuCl 2 (PPh 3 ) 4 , RuH 2 (PPh 3 ) 4 , and RhCl(PPh 3 ) 3 .

7. The process of claim 1 , wherein the weight ratio of the compound having Formula (I) to the transition metal catalyst is from about 1:0.0001 to about 1:0.1; and the weight ratio of the compound having Formula (I) to the metal scavenger is from about 1:0.005 to about 1:0.5.

8. The process of claim 1 , wherein the metal scavenger comprises a functional group chosen from acetyl, amide, amine, amino, guanidine, imidazole, imine, mercaptophenyl, phosphonic acid, trimercaptotriazine, triamine, thiol, thiourea, and combinations thereof.

9. The process of claim 1 , wherein steps (a) and (b) are conducted in the presence of a protic or an aprotic solvent; steps (a) and (b) are conducted at a temperature from about 10° C. to about 120° C.; and step (b) is conducted at a pH from about 0 to about 7.

10. The process of claim 1 , wherein the process is a one-pot synthesis.

11. The process of claim 1 , wherein the substantially metal-free compound of Formula (II) has a metal content of less than about 100 ppm.

12. The process of claim 1 , wherein the optical activity of the compounds having Formulas (I) and (II) is (−) or (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is selected from the group consisting of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule.

13. The process of claim 1 , wherein the process is a one-pot synthesis; the transition metal catalyst is chosen from a transition metal element, a transition metal salt, and a transition metal complex; the metal of the transition metal catalyst is chosen from iridium, nickel, osmium, palladium, platinum, rhodium, and ruthenium; the weight ratio of the compound having Formula (I) to the transition metal catalyst is from about 1:0.0001 to about 1:0.1; the metal scavenger comprises a functional group chosen from acetyl, amide, amine, amino, guanidine, imidazole, imine, mercaptophenyl, phosphonic acid, trimercaptotriazine, triamine, thiol, thiourea, and combinations thereof; the weight ratio of the compound having Formula (I) to the metal scavenger is from about 1:0.005 to about 1:0.5; steps (a) and (b) are conducted in the presence of a protic solvent and at a temperature from about 10° C. to about 120° C.; the weight ratio of the protic solvent to the compound having Formula (I) is from about 0.5:1 to about 20:1; step (b) of the process is conducted at a pH from about 0 to about 7; the compound having Formula (II) is separated from the metal scavenger by filtration after step (b); the compound having Formula (II) has a yield of at least about 60%; and the compound having Formula (II) has a metal content of less than about 100 ppm.

14. The process of claim 13 , wherein the optical activity of the compounds having Formulas (I) and (II) is (−) or (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is selected from the group consisting of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule.

15. The process of claim 3 , wherein the process is a one-pot synthesis; the transition metal catalyst is a bis(allyl)-ruthenium complex; the weight ratio of the compound having Formula (I) to the bis(allyl)-ruthenium complex is from about 1:0.001 to about 1:0.05; step (a) of the process is conducted in the presence of a protic solvent comprising ethanol and water and at a temperature from about 65° C. to about 90° C.; the weight ratio of the protic solvent to the compound having Formula (I) is about 1:1 to about 10:1; the metal scavenger has a thiol functional group and is attached to a silica-based solid phase; the weight ratio of the compound having Formula (I) to the metal scavenger is about 1:0.02 to about 1:0.1; step (b) of the process is conducted in the presence of a protic solvent comprising ethanol and water, at a pH from about 2 to about 3, and at a temperature from about 60° C. to about 105° C.; the compound having Formula (II) is separated from the metal scavenger by filtration after step (b); the compound having Formula (II) has a yield of at least about 80%; and the compound having Formula (II) has a metal content of less than about 50 ppm.

16. The process of claim 15 , wherein the optical activity of the compounds having Formulas (I) and (II) is (−) or (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is selected from the group consisting of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule.